Better Treatments for Disrupted Circadian Rhythm

Newswise �?A Valparaiso University biochemistry student has helped make a key discovery in a class of proteins that could play a critical role in designing better treatments for diseases associated with disrupted circadian rhythm �?the roughly 24-hour cycle a person’s body goes through. Valparaiso is a member of the Council on Undergraduate Research.

Newswise �?Amanda Nosie, a senior from Plainfield, Ind., spent the past summer doing research at Eli Lilly & Co. with Valparaiso alumnus Keith Stayrook (�?4), and their paper “Identification of Heme as the Ligand for the Orphan Nuclear Receptors REV-ERBα and REV-ERBβ�?is being published this fall in the prestigious scientific journal Nature Structural and Molecular Biology. Only a handful of undergraduate students have co-authored papers appearing in the journal.

Their paper explores the function of two receptors �?REV-ERBα and REV-ERBβ �?belonging to a class of proteins known as nuclear hormone receptors (NHRs) that are bound and activated by hormones such as estrogen and vitamin D, thus allowing them to work. While most NHRs are well-defined and often the targets for pharmaceutical drugs, the two receptors investigated by Nosie and Stayrook until now were considered “orphans�?as no known hormones �?often referred to as ligands �?had been identified as binding to them since their discovery two decades ago.

Yet, Stayrook said, scientists knew that the two receptors held important physiological roles in the regulation of the body’s circadian rhythm and likely had physiological ligands.

Therefore, the discovery by Nosie and Stayrook that the two receptors are indeed ligand-regulated and that the porphyrin heme behaves as a reversible activator for the receptors could help scientists design new drugs treating diseases associated with disturbed circadian rhythm, including psychiatric and metabolic disorders, as well as cancer.

During her research internship, Nosie completed a critical final experiment that confirmed heme-binding to the two receptors activated their biological functions.

Nosie, who has been interested in pharmaceutical research since high school, enjoyed the opportunity to work in a laboratory at a leading pharmaceutical company and see the results of her research published.

“I learned a great deal about more laboratory procedures, especially cloning and cell culture, and I got additional experience in designing experiments,�?she said.

Stayrook said direct experience with the scientific process is a critical stepping stone for young scientists.

“All scientists understand and realize this important evolving process begins at a young age, and having good learning opportunities into the scientific research process early in one’s career is by far one of the most defining moments for many scientists,�?he said. “When one can create such an opportunity and help develop a young scientist from your alma mater, it certainly enhances the gratification.�?

Nosie said her research at Lilly was helped by previously working with VU chemistry professor Dr. Thomas Goyne on a project studying the microbe Shewanella algae �?which could help prevent radioactive contamination from spreading through soil and groundwater at sites where nuclear weapons have been tested or built.

“My research with Dr. Goyne helped prepare me to conduct lab work, and many of the basic procedures I used on the Shewanella project were also applicable to the research project last summer,�?Nosie said. “I also think it was helpful to get a feel for working in a research lab.�?